ANZCTR



Efficacy of Botulinum Toxin A on Walking and Quality of Life in Post-Stroke Lower Limb Spasticity- a randomized double-blind placebo controlled Study

Anupam Datta Gupta, Simon Koblar, Renuka Visvanathan, Ian Cameron and David Wilson

Background

Stroke is a leading cause of death and the third most common cause of long-term adult disability in the developed world (1). Stroke is Australia’s second biggest killer after coronary artery disease and a leading cause of disability. The Stroke Foundation of Australia estimates there were 60,000 new and recurrent stroke cases in Australia in 2011 (2). The cost of stroke burden is $2.14 billion a year. In recent decades, significant advances have taken place in diagnosis, management and prevention of stroke.  However, stroke survivors continue to face great challenges due to long-term impairments and many lose their ability to live independently. Motor impairment is the most common and widely recognised impairment caused by stroke (3). Motor impairments manifest as limitation of muscle control, body movements and associated functions, and typically affect one half of the body - the arm and the leg. More than two thirds of stroke survivors develop impaired motor function and post-stroke spasticity. The prevalence of spasticity following stroke is between 17% and 46 % (4).  Post-stroke spasticity can significantly restrict stroke survivor’s functional ability, their activities of daily living and can diminish their quality of life (5). Spasticity has been defined as “motor disorder characterised by velocity-dependent increase in tonic stretch reflexes (muscle tone) with exaggerated tendon jerks resulting from hyper excitability of the stretch reflex, as one component of the upper motor neuron syndrome.” (6).  The effect of spasticity is profound.  Following stroke, the body goes into safe mode (spasticity) causing loss of movement control, painful spasms, abnormal posture, increased muscle tone, and an overall decline in the function of muscles (7). There is strong evidence that exercise following a stroke can rewire the brain and has neuro-protective effects by activating specific neural circuits and increasing molecules that enhance synaptic plasticity (8). Repetitive task specific training will produce the behavioural experience, that is the most potent modulator of brain plasticity (9). Post stroke exercise and motor re-education is therefore an important rehabilitation tool. Langhammer (8), showed that post stroke motor impairments have a major impact on motor function, balance, gait, mobility, and activities of daily living and the patients improve with training. The first problem to deal with, however, is the effects of spasticity (muscle stiffness) on muscle tone and flexibility, which interferes with, or stops the exercise prescription. Exercise will also benefit the patients with motor impairment other than spasticity. There is, however good evidence that BoNT-A has clinical benefit in treating the mechanical effects of spasticity (10,11).  The key to improving stroke outcomes is first; to deal with spasticity in those patients who suffer it, then implement a structured exercise program and rehabilitation.   This study will detail such a plan.

Our recent systematic review of 2011 studies of spasticity treatment, using botulinum toxin (BoNT-A) in the lower limb, showed only five studies fitted our criteria of randomised controlled trials describing the efficacy of BoNT-A on walking in post-stroke lower limb spasticity (12). There were also major design problems with these five studies including sample selection, study inclusion criteria, outcome measures, administration of BoNT-A, and methods of statistical analysis (13,14,15,16,17). From the studies done to date on the lower limb, the evidence base for improvement of active functions such as gait velocity, walking distance and quality of life using BoNT-A for lower limb post stroke spasticity, is not robust.  The underlying aim of this study is to provide an evidence based intervention, with an appropriate sample, rigorous study design and much improved management of participants and intervention elements.

Why Concentrate on the Lower Limb?

Improved walking is one of the highest priorities for people living with stroke (18). Walking is a mode of bipedal locomotion in which both feet remain in contact with the ground, followed by a period of single stance on one limb while the other limb is swung forward. Post stroke patients with equinovarus deformity are unable to achieve proper contact with the ground resulting in poor stance on the affected leg and lose the heel toe rhythm of walking due to plantarflexion/inversion of the foot. Most of the phases of gait such as initial contact, loading response, mid stance, push off (stance phase), initial swing, and mid swing (swing phase) are affected. The awkward positioning of the foot and spasticity impairs balance, transfer, stride, gait and mobility besides causing spasm and pain. The awkward positioning can also lead to fall and fractures (19). There is significant human and economic cost of spasticity (20). Inability to walk is a predictor of losing independence and/or discharge to a nursing home (21). Above all it contributes to a range of adverse health outcomes including mortality (22). In the upper limbs, there is no related dependence of operation. If one side of the body is affected, following stroke, the other side can be trained to compensate.  In the lower limb, the dependence of both legs is essential for standing, maintaining balance, transferring from sitting to standing position and walking ability.  This emphasises the fact that rehabilitation of the lower extremities is very important.

Botulinum Toxin

In most countries, the use of the botulinum toxin (BoNTA) is first line treatment for post stroke spasticity in the upper limb.  The PBS in Australia and many other countries approves BoNT-A for post stroke upper limb spasticity, but not for lower limb spasticity.  This is largely because of the low-level evidence available from clinical trials. As mentioned above our systematic review could find only five randomised controlled trial (RCT) studies that addressed the issue for the lower limb.  Most of the studies addressing the use of BoNT-A in the medical literature have concentrated on the upper limb. Recently (in 2016) the Federal Drug Administration (FDA) has approved the toxin for post stroke lower limb spasticity in the United States (23). There is still, however, a documented unmet need for level 1 research studies demonstrating its effective use for post stroke lower limb spasticity (24), which agrees with the conclusion of our systematic review. Gait, balance and transfer are important lower limb functions and critical for a person’s independence and participation in society, as is identified by the by the World Health Organisation report on disability (25). Studies have shown that treating spasticity with BoNTA-A is cost effective (26, 27, 28).

In our systematic review, we contend that the evidence base for improvement of active function such as gait velocity, walking distance and quality of life, using BoNT-A for lower limb post stroke spasticity, is not methodologically robust (12). What is required is an RCT that is epidemiologically sound in its sample size and quality; choosing a sample that does not have significant impairment; is designed to study functional outcomes, including improved quality of life and activities of daily living; uses appropriate statistical methods in design and analysis; is precise in targeting the involved muscle with guided (electromyogram/EMG) injection, and; combines the reduction in spasticity with a solid rehabilitation program to overcome muscle tone, weakness and thus restores function.  This study will address these issues in its methodology.  Although BoNT-A has not been approved for use on the lower limb by Pharmaceutical Benefit Scheme in Australia, the evidence for its effect on spasticity is already provided from extensive literature on the upper arm.  We believe that this effect can be delivered to post-stroke lower limb spasticity and facilitate a structured rehabilitation program with improved outcomes. This has been a major failure in the previous RCT’s. 

Study Methodology

Objective:

This proposed study will address an area of stroke rehabilitation to provide the evidence base for the use of botulinum toxin type A in improving gait velocity/walking distance and in quality of life amongst post stroke patients with lower limb spasticity. The design of the study is a randomised controlled trial of the botulinum toxin against placebo on the traditional (reduction in spasticity) and new health outcome parameters related to lower limb functioning (walking) and quality of life.

Endpoints:

Primary/co-primary- Gait velocity/walking distance

Secondary- Spasticity measured by modified Ashworth Scale, Timed Up and Go (TUG), Berg Balance score, ABILICO score, Goal Attainment Scale (GAS), 2 Minute Walk Test, Quality of Life SF 12 (Rand version)

Hypothesis:

The primary study hypotheses will seek to identify differences between intervention and control group first, in gait velocity/walking distance, quality of life (including physical and mental health) and in spasticity, other functional parameters listed below and in activities of daily living.

Study design and rationale:

The study is a single centre (multiple sites), double- blind, randomized, placebo- controlled trial (RCT) of one set of intramuscular injections of botulinum toxin A with one set of injections of placebo. Subjects will be randomly assigned to receive a total dose of 200-400 units of botulinum toxin A (Botox, Allergan) or an equal volume of placebo (saline) into the spastic muscles. Active and placebo drugs will be identical in appearance. The rationale of the study design is to prove the efficacy of the Botox in improving lower limb function- a RCT is the gold standard for proving the efficacy of a drug.

Participant recruitment

Participants will be recruited from the acute stroke units, rehabilitation wards and spasticity clinics across Adelaide, South Australia, including Royal Adelaide Hospital, Hampstead Rehabilitation Centre, Modbury Hospital, Repatriation General Hospital and Flinders Medical Centre. Patients will also be recruited from the community through their GP or physiotherapists.

Inclusion criteria

• Male or female subjects aged 20 to 80 years of age are eligible for this study if they had a stroke resulting in focal spasticity in the knee causing stiff knee and/or equinovarus deformity, as demonstrated by a score of more than 3 for quadriceps (rectus femoris), gastrocnemius, soleus, tibialis posterior, flexor hallucis longus or flexor digitorum longus on the Modified Ashworth Scale.

• All patients should be walking normally prior to stroke. Any patients with lower limb spasticity (MAS 3+) resulting in a limp, or any difficulty in weight bearing on the leg or walking such as reduced speed of gait following stroke will be included. 

The Modified Ashworth Scale denotes 0 for normal muscle tone and a score of 4 denotes that the affected part(s) are rigid in flexion or extensions. The criteria for enrolment will include difficulty in lower limb functioning such as walking, balance, and transfers in patients with post-stroke lower limb spasticity. Patients with lower limb spasticity of Modified Ashworth (MAS) Scale of 3+ in any muscle group will be included in the study.

Exclusion criteria

• This study will exclude patients with significant speech or cognitive impairment

• Significant lower limb problems such as fracture or arthritis, evidence of fixed contracture

• Use of botulinum toxin type A in the previous six months, other non-stroke neurological disorders causing lower limb spasticity

• Significant illness, such as malignancy, or contraindication to botulinum toxin type A, will exclude people from the study.

• Pregnant and lactating mothers will also be excluded from the study.

• Individuals with osteoarthritic knee or hip having pain score of 3/10 or more on VISUAL Analog Scale will be excluded.

• Individuals with significant depression (Geriatric Depression Scale (12 or more/15) and Beck Depression Inventory (30 or more/63) will be excluded from the study.

• Individuals on antispasticity medications such as Baclofen, Tizanidine, Dantrolene, Diazepam will be excluded from the study.

Withdrawal Criteria

Withdrawal criteria will cover subjects unable to comply with the study protocol, for any reason, or lost to follow up after 3 attempts of contact.

Treatment and blinding

The intervention group will receive BT injection (up to 400 units of Botulinum toxin, Allergan reconstituted with 2ml of normal saline) into the lower limb spastic muscles. The participants in the placebo group will be receiving identical looking placebo injections. Botulinum toxin is available in powder form and is reconstituted with normal saline before injection and is a colourless solution. The study physician administering the injection and the patient will be blinded to the syringe contents. The pharmacist who is external to the study will be providing the injection and will not be blinded. Participants in both the intervention and the placebo group will receive the same structured physiotherapy program designed to improve walking and other lower limb functions. The null hypothesis could be the fact that the injection of Botox does not improve lower limb function and quality of life.  

Dosage and administration

The intervention group will receive BT injection (up to 400 units of Botulinum toxin, Allergan reconstituted with 2ml of normal saline) into the lower limb spastic muscles. The spastic muscles will be identified clinically and confirmed by EMG, (DANTEC CLAVIS). Maximum dose of Botox per session is 400 units (approved by TGA). The dose is dependent on the number of muscles and the size of the muscle involved. Post-stroke spasticity may involve Rectus Femoris spasticity requiring about 200 units. Most common deformity in post-stroke patients is equinovarus deformity. In an equinovarus deformity (caused by Gastrocnemius/soleus, Tibialis Posterior) the implicated muscles may require the following dosage. Gastrocnemius/Soleus-causes equinus deformity (plantarflexion)- may need up to 300 units. Tibialis Posterior – causes equinus and varus deformity- may need up to 200 units. Flexor Pollicis Longus and Flexor Digitorum Longus (causes clawing of great toe and other toes) - may require 100- 150 units each.

Allowed and disallowed medications and treatments

It is important that all participants are also not currently taking any spasticity reducing medication as the purpose of the study is to assess the effect of BoNT-A in providing improved outcomes from the subsequent intervention. Concomitant treatment for other health conditions can continue.

Study procedures

The participants with post-stroke lower limb spasticity will be initially evaluated by the study physician (principle investigator) for their eligibility. The base line assessments will be carried out

including spasticity measurements by Modified Ashworth Scale and Tardieu scale. Lower limb functional assessments will be made using Timed Up and Go (TUG) test, Berg Balance Score, Goal Attainment Scale (GAS), 2 Minute Walk Test, ABILICO, Gait analysis in the Gait Rite machine and Quality of Life Scores (SF 36). Participants will undergo stratified randomization (ischaemic versus haemorrhagic stroke) by block permutation. The participants will be injected with the drug or the placebo (identical looking) prepared by the pharmacist external to the study. The spastic muscles will be identified by the EMG machine (DANTEC CLAVIS). The study physician, physiotherapist and the patients will be blinded to the syringe contents. Following injection of the drug and placebo, patients will be followed up. All the participants will be provided with standard physiotherapy (similar therapy in terms of duration, intensity and frequency).

Routine Physiotherapy and Standard Care

All participants will receive routine physiotherapy and standard care. This will include stretching, balancing, strengthening exercises and gait retraining. Gait retraining (task specific) will include walking on the level ground and then progressing to walking on inclines and different surfaces. We will aim to standardize the therapy in terms of frequency (two sessions/week in the Physiotherapy department at the Queen Elizabeth Hospital, duration (45 minutes each session) and intensity (4-6 in Borg’s Scale of Perceived Exertion). Patients will be provided with orthotics as clinically indicated. Patients will also be given a home exercise program. Phone calls will be made monthly, and the participants will be given encouragement, advised to keep up activities, not putting on weight and will also be advised on diet.

Study tools and Evaluations

Participants will be assessed at baseline, 3 weeks, 3 months and 5 months post intervention by the study physician (principle investigator), physiotherapist and the registrar who are blinded to the allocation. The primary outcome of the study is improvement of gait velocity in the Gait Rite Machine (electronic walkway) and will be recorded as centimeters per second or the distance during 2 min walk. Assessments the secondary outcomes as described above will also be carried out.

Site of procedures and evaluations

The study will be carried out in the Spasticity clinic run from the new Rehabilitation and Allied health building at the Queen Elizabeth Hospital. Follow up reviews will also be carried out in the clinic and in the Rehabilitation Medicine department at The Queen Elizabeth Hospital.

Study drug handling

The Queen Elizabeth Hospital Pharmacy department will handle the medications and will prepare the identical looking blinded syringes

Sample Size Calculation

In most of the RCT’s included in our systematic review serious sample inadequacies were identified. Chief among these was the problem of inadequate sample calculations for repeated measures design.  In studying a number of outcome measures over time the authors failed to calculate sample size based on repeated measures criteria. The sample size for this study is, therefore, based on repeated measures design of baseline and three follow-ups at 3 weeks, 3 months and 5 months post intervention. In a repeated measures ANOVA, the within subjects factor of time allows for a common time effect in both the treatment and control groups, the treatment main effect adjusts for the differences between the treatment and control groups at baseline, and the interaction between treatment and time tests the treatment effect. In including estimates of the variance and correlations between measures the largest sample size calculation for the outcome measures proved to be gait speed and allowing for a power of 90% and significance level of 0.5 a sample size of n=30 was required for each group. Allowing for dropouts in the study we increased the sample size to n=40 in each group giving a final study sample of n=80.

Statistical Methods

The data will be summarised using means with standard deviations and medians with inter-quartile range. Group differences in change in gait speed will be assessed using the Student t-test or the Wilcoxon (Mann-Whitney) test as appropriate. Generalised linear models will be used to assess group effects with adjustment for known confounders such as gender and age. All tests will be two-tailed and assessed at the 5% alpha level.  Other advanced statistical tests and modelling techniques will be selected as appropriate and informed by the univariate analyses.

Figure 1: Study Design- Randomised Controlled Trial

↓

↓

↓ ↓

↓ ↓

↓ ↓

↓ ↓

REFERENCES

1. Stinear CM, Barber PA, Petoe M, Anwar. S, Byblow WD. The PREP algorithm predicts

potential for upper limb recovery after stroke. Brain 2012: 135; 2527-2535.

2. stats.

3. Langhorne P, Coupar F, Pollock A. Motor recovery after stroke: a systematic review.

Lancet Neurol. 2009: 8; 741-754.

4. Zorowitz RD, Gillard PJ, Brainin M. Poststroke spasticity-Sequelae and burden on stroke

survivors and caregivers. Neurology 2013: 80 (Suppl 2); S27-S34.

5. Sunnerhagen KS, Olver J, Francisco GE. Assessing and treating functional impairment in

post-stroke spasticity. Neurology 2013: 80 (Suppl 2); S35-S44.

6. Lance JW. Symposium synopsis. In: Feldman RG, Young RR, Koella WP (editors).

Spasticity: disordered motor control. Miami: Year Book Medical Publishers; 1980: 485–494.

7. Stroke Smart. Spasticity: How to tone it down after a stroke. . Accessed

10th March 2017.

8. Langhammer B, Lindmark B. Functional exercise and physical fitness post stroke: The

importance of exercise maintenance for motor control and physical fitness after stroke.  Stroke

Res Treat 2012; 2012: 1-9.

9. Nudo R. Recovery after brain injury: mechanisms and principles. Front Human Neurosci

2013; 7:1-14.

10. Moore AP. Botulinum toxin (BoNT-A) for spasticity in adults. What is the evidence? Eur J

Neurol. 2002 May;9 Suppl 1:42-7; discussion 53-61.

11. Teasell R, Foley N, Pereira S, Sequeira K, et al. Evidence to practice: Outline toxin in the

treatment of spasticity post stroke.  Stroke Rehab 2012; 19(2): 115-121.

12. Gupta AD, Chu WH, Howell S, Chakrabarty S, Koblar S, Visvanathan R, Cameron I, Wilson

D. Efficacy of Botulinum Toxin on Walking and Quality of Life in Post-Stroke Lower Limb

Spasticity. Under Review MJA.

13. Burbaud P1, Wiart L, Dubos JL, Gaujard E, Debelleix X, Joseph PA, Mazaux JM, Bioulac B,

Barat M, Lagueny A. A randomised, double blind, placebo controlled trial of botulinum toxin

in the treatment of spastic foot in hemiparetic patients. J Neurol Neurosurg Psychiatry 1996

Sep;61(3):265-9.

14. Pittock, S. J., et al. (2003). "A double-blind randomised placebo-controlled evaluation of

three doses of botulinum toxin type A (Dysport) in the treatment of spastic equinovarus

deformity after stroke." Cerebrovasc Dis 15(4): 289-300.

15. Johnson, C. A., et al. (2004). "The effect of combined use of botulinum toxin type A and

functional electric stimulation in the treatment of spastic drop foot after stroke: a preliminary

investigation." Arch Phys Med Rehabil 85(6): 902-909.

16. Kaji, R., et al. (2010). "Botulinum toxin type A in post-stroke lower limb spasticity: a

multicenter, double-blind, placebo-controlled trial." J Neurol 257(8): 1330-1337.

17. Tao, W., et al. (2015). "Gait improvement by low-dose botulinum toxin A injection treatment

of the lower limbs in subacute stroke patients." Journal of Physical Therapy Science 2014;

27(3): 759-762.

18. Bohannon RW, Andrews AW. Smith MB. Rehabilitation goals of patients with hemiplegia.

Int J Rehabil Res. 1988; 11(2): 181-183.

19. Esquenazi A. Falls and Fractures in Older Post-Stroke Patients with Spasticity: Consequences

and Drug Treatment Considerations. Clin Geriatrics. 2004; 12:1-9.

20. Esquenazi A. The Human and Economic Burden of Post stroke Spasticity and Muscle

Overactivity. J Clin Outcome Management. 2011; 18: 607-614.

21. Wade DT, Skilbeck CE, Wood VA, Langton Hewer R. Long-term survival after stroke. Age

and Ageing. 1984;13(2): 76-82.

22. Newman AB, Simonsick EM, Naydeck BL, et al. Association of long-distance corridor walk

performance with mortality, cardiovascular disease, mobility limitation, and disability.

JAMA. 2006; 295(17): 2018-2016.

23.

24. Martin A, Abogunrin S, Kurth H, Dinet J. Epidemiological, humanistic, and economic

Burden of illness of lower limb spasticity in adults: a systematic review. Neuropsychiatr Dis

Treat 2014; 10:111-122.

25. WHO report on disability: whqlibdoc.who.int/publications/2011/9789240685

215_eng.pdf: 95

26. Lundstrom E, Sits A, Borg J, Terent A. Four-fold increase in direct costs of Stroke survivors

with spasticity compared with stroke survivors without spasticity: the first year after the

event. Stroke 2010; 41:319-324.

27. Wallesch CW, Maes E, Lecomte P, Bartels C. Cost-effectiveness of botulinum toxin type A

injection in patients with spasticity following stroke: a German perspective. Eur J Neurol

997;4: S53–S57.

28. Ward A, Roberts G, Warner J, Gillard S. Cost-effectiveness of botulinum toxin type A in the

Treatment of post-stroke spasticity. J Rehab Med 2005; 37:252-257.

-----------------------

Screening Recruitment

Baseline measurement

Randomization

N = 80

INTERVENTION

Routine physiotherapy and standard care

+

Injection of BT

N=30

CONTROL

Routine physiotherapy and standard care

+

Placebo injection

N=30

Follow – up

3 weeks

Follow - up

3 weeks

Follow - up 3 months

Follow - up 3 months

Follow - up 5 months

Follow - up 5 months

................
................

In order to avoid copyright disputes, this page is only a partial summary.

Google Online Preview   Download